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Background: It is difficult to determine the prognosis of granulosa cell tumors (GCT) at the time of diagnosis., Methods: The nuclear DNA content of 17 patients with ovarian GCT was investigated by flow cytometry using paraffin-embedded tissue. Nuclear area (NA), nuclear perimeter (NP), and nuclear shape factor (NSF) were measured by an image analyzer using hematoxylin- and-eosin-stained sections., Results: The follow-up period of the patients ranged from 2 months to 11 years. Thirteen tumors were diploid or near diploid, whereas one was tetraploid, and three were aneuploid. Two tumors had varying degrees of DNA content heterogeneity. Crude survival of the patients with an euploid tumor (13 diploid, 1 tetraploid) was more favorable than that of the patients with an aneuploid tumor. Patients with S-phase fraction (SPF) greater than 10% or DNA content heterogeneity experienced disease recurrence or metastasis. A significant difference was observed in NA and NP between those with and without metastasis., Conclusions: Our results indicate that DNA aneuploidy, large SPF, DNA content heterogeneity, and large NA and NP are adverse prognostic factors in GCT. Thus, flow cytometric and morphometric measurement may provide a rapid and valuable method to predict the biologic behavior of GCT.

Sclerosing stromal tumors are rare, benign ovarian neoplasms of unknown etiology and histogenesis. Three sclerosing stromal tumors were evaluated by immunohistochemistry and electron microscopy and were compared to two thecomas and nonneoplastic ovarian mesenchymal tissue. The sclerosing stromal tumors and thecomas were positive for muscle-specific actin; immunoreactivity was intense in the cellular areas of the sclerosing stromal tumors and focal in the thecomas. This antigen was expressed in nonneoplastic stroma predominantly in a perifollicular (theca externa) distribution. Two sclerosing stromal tumors and both thecomas were vimentin positive. Desmin was present in nonvascular cells in one of each tumor type. Expression of vimentin diffusely and of desmin focally was present in nonneoplastic cortical stroma and surrounding follicles. All specimens were nonreactive for cytokeratin. Electron microscopy supported differentiation toward smooth muscle in the sclerosing stromal tumors but not in the thecomas. Such differentiation included aggregates of cytoplasmic filaments with interspersed dense bodies, pinocytotic vesicles, and basal lamina. Delicate, long processes interconnected cells, often with primitive junctions, in the hypocellular foci. Cytoplasmic lipid, which was present in the thecomas, was not well developed in the sclerosing stromal tumors. It is proposed that a population of muscle-specific actin-positive elements exists in the theca externa--the perifollicular myoid stromal cell--and that sclerosing stromal tumors may originate from them. Sclerosing stromal tumors and thecomas share many antigenic determinants and morphologic features and thus are probably closely related entities.

The ultrastructure of a virilizing granulosa-theca cell tumor is reported. Although the histologic appearance is characteristic of a granulosa-theca tumor, several tumor cells contain crystalloids of Reinke which have not been associated with sex-cord-stromal tumors, but which are often present in ovarian hilus cells and Leydig cells. The steroidogenic cell in this case displays many fine structural features common to mammalian steroidogenic cells, namely abundant smooth endoplasmic reticulum, a dispersed Golgi, mitochondria with tubular cristae, and lipid droplets. Other features of this cell, which contains crystalloids of Reinke, more closely resemble those of a theca-lutein cell than a granulose-lutein or hilus cell and support a stromal origin. However, this tumor illustrates the striking overlap in morphologic features and function among granulosa, theca, hilus, and Leydig cells.

Three ovarian thecomas were studied by ultrastructural and immunohistochemical techniques. In each tumor, a small number of tumor cells stained for estradiol. Vacuolated as well as plump non-vacuolated tumor cells were positive, but spindle-shaped cells were negative. Ultrastructural examination showed two principle cell types. Type I cells were immature mesenchymal cells that differed from typical steroid-secreting cells because only a minority had conspicuous smooth endoplasmic reticulum, although mitochondria often had tubular cristae. Type II cells were distinguished by abundant intermediate (10-nm) microfilaments and round mitochondria with incomplete cristae and empty centers. Focal smooth muscle differentiation was present in each tumor. Adherens-type intercellular junctions, including desmosomes in one case, and degenerate cells with markedly vesiculated cytoplasmic membrane systems were also present. Lipid was not abundant, but it was more conspicuous in degenerate cells and in type II cells. Thecoma cells thus closely resemble both ovarian stromal cells and theca interna cells, which are known to be capable of steroidogenesis. The localization of estradiol in a minority of tumor cells in each thecoma suggests that thecoma cells, too, are capable of steroid synthesis and supports the popular concept that hyperestrogenism in patients with thecomas may be the result of estradiol secretion by these tumors.

A nonluteinized granulosa cell ovarian tumor and a purely luteinized ovarian tumor, induced by gonadotropin stimulation in mice, were studied ultrastructurally to obtain evidence concerning the possible origin of these tumors, whether from granulosa cells only or from granulosa and theca. Evidence including the presence of cells sharing features of both nonluteinized and luteinized cells, the presence of desmosomes and other junctional complexes in both cell types, and the presence of partially extracted lipid droplets in the luteinized cells suggests that the luteinized cells represent granulosa-lutein cells rather than theca-lutein cells. These findings are consistent with the concept that these tumors represent a spectrum of differentiation from nonluteinized granulosa cells to luteinized granulosa cells. The lack of theca and theca-lutein cells in both tumors implies that theca cells are not involved as progenitor cells.

A case of low-grade ovarian stromal sarcoma in a postmenopausal woman is described. Although pelvic recurrences of the tumor followed 5 and 7 years after the original surgery, the patient has remained well and without evidence of tumor 3 years since the last operation. Histopathologic, electronmicroscopic, and hormonal studies are described. There was evidence of estrogenic stimulation by the theca elements of the tumor in this patient. Cases previously reported in the world literature as malignant thecoma were analyzed, and most of them were considered inadequately documented; indeed most of them were probably either sarcomatoid granulosa cell tumors, stromal sarcomas, or fibrosarcomas. If a thecoma ever becomes malignant, the tumor cells dedifferentiate so that they cannot be recognized any longer as theca cells; instead, they proliferate as a stromal sarcoma or fibrosarcoma. It is proposed, therefore, that the term "malignant thecoma" not be used. On the other hand, very rare malignant ovarian stromal tumors do exist, consisting of undifferentiated stromal cells, fibroblasts, and theca cells, which can show evidence of hormonal activity.

Granulosa theca cell tumor (GTCT) in the premenarche accounted for 7% of all ovarian tumors treated at the Children's Hospital Medical Center from 1928 through 1979. The average age of the ten girls at the time of diagnosis was 5 years (range 11 months-121/2 years) with precocious "pseudopuberty" and an abdominal mass being the most common presentation. GTCTs were solitary (five right, five left) with an average diameter of 12.1 cm. Histologic examination showed a predominantly diffuse or solid pattern with prominent luteinization; Call-Exner bodies and folded ("coffee-bean") nuclei were inconspicuous. Ultrastructural examination of one GTCT confirmed the presence of both granulosa and theca components with the latter showing extensive luteinization; estradiol, testosterone and prolactin were demonstrated in the same tumor using immunologic techniques. The average follow-up time was 21 years with nine of the ten patients being followed for more than ten years. Salpingo-oophorectomy resulted in cures despite the occurrence of tumor spillage in two patients. The prognosis for GTCTs in the premenarche appears more favorable than for those occurring in adulthood, but further study is needed to completely define their full biologic potential; the significance of subsequent breast cancer in two long-term survivors merits further investigation as well.

Two typical cases of sclerosing stromal tumours of the ovary are studied ultrastructurally, and the findings are correlated with the clinical data. One of the cases, with predominantly fibroblastic morphology, was asymptomatic. The second case, rich in cells with steroid-secreting features, had polymenorrhoea disappearing after removal of the tumour. The Authors suggest that clinical symptoms of sclerosing stromal tumour of the ovary depend from the degree of differentiation reached by the tumour cells.

Seventeen ovarian sex cord-stromal tumors that contained bizarre nuclei are reported. The patients, two of whom were pregnant, ranged in age from 14 to 72 years (average, 47 years). The tumors, two of which had ruptured, were all Stage Ia. On microscopical examination, all the tumors had areas typical of one of the subtypes of ovarian sex cord-stromal tumors but, in addition, had foci where the cells had enlarged bizarre nuclei. Multinucleated giant cells were present in 12 cases and were of the floret-type in five of them. Apart from the presence of the bizarre nuclei and giant cells, the microscopical appearance and the mitotic rate of the tumors were similar to those of sex cord-stromal tumors in general. Eight tumors were classified as granulosa cell tumors, seven as Sertoli-Leydig cell tumors, and two as thecomas. Eleven patients who have been followed for 3-21 years (average, 9.7 years) postoperatively are alive and free of disease. Two patients have been lost to follow-up, and four have been treated too recently for a meaningful follow-up. The bizarre changes in these tumors resemble those seen in the uterine leiomyoma with bizarre nuclei and, like them, are probably degenerative. Their presence does not appear to alter the prognosis of the underlying tumor in view of the results of this small series.

A case of malignant luteoma was found in a 3-year-old Landrace sow. A large neoplastic mass was present in the left ovary and small neoplastic nodules were seen in the right ovary. There were metastatic lesions in the diaphragmatic peritoneum and heart. The neoplastic cells were extremely pleomorphic and among them relatively large cells predominated. The neoplastic cells had lipid droplets, membranous structures, intermediate filaments and lipofuscin granules in their cytoplasm.

To establish the cell type responsible for the production of estrogens in an ovarian tumor, seven thecomas, three granulosa cell tumors and one fibroma were studied with electron microscopy. The secretion of estrogens by the tumor was determined by measuring the plasma levels of estrogens in the ovarian and cubital veins of some patients and examining the histology of the endometria. Polygonal cells with abundant smooth endoplasmic reticulum (SER) at the ultrastructural level were found in the tumors of patients with clinical signs of hyperestrogenism. It is likely that these cells are the site of steroidogenesis, which is known to be reflected by SER in the cells of the human corpus luteum.